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Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission.

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common β chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR α chain, encoded in the X-chromosome pseudoautosomal region 1.

Objective To investigate the role of CXCL13 in the development and pathogenesis of collagen-induced arthritis (CIA), and to determine the mechanisms involved in the modulation of arthritogenic response by CXCL13 neutralization. Methods Mice were immunized with type II collagen (CII) and treated with anti-CXCL13 or control antibodies during boosting. Mice were monitored for the development and severity of arthritis. The effects of CXCL13 neutralization on immune response to CII were evaluated by cytokine production by CII-specific T cells and CII-specific antibody production. Follicular response in the spleen and in synovial tissue was determined by in situ immunohistology. Results Mice receiving neutralizing antibodies to CXCL13 developed significantly less severe arthritis compared with mice injected with phosphate buffered saline or control antibodies. Follicular response both in the spleen and in synovial tissue was inhibited by anti-CXCL13 treatment. Injection with anti-CXCL13 antibodies did not significantly affect antigen-specific recall lymphocyte proliferation or type 1 cytokine production in vitro. Antibody response specific to CII was not inhibited by anti-CXCL13 treatment. However, anti-CXCL13 treatment induced significantly higher levels of interleukin-10 production after in vitro CII stimulation. Conclusion Neutralization of CXCL13 inhibits the development of CIA and reduces follicular response in both lymphoid and nonlymphoid tissues. These findings may have important implications regarding the pathogenesis and treatment of autoimmune arthritis.

Objective To test the hypothesis that constitutive expression of Nur77 in the T cell lineage will suppress the development and pathogenesis of collagen-induced arthritis (CIA) and to understand the mechanisms by which Nur77 overexpression influences the arthritogenic response to type II collagen (CII). Methods Nur77-transgenic and wild-type C57BL/6 mice were immunized with CII and were monitored for the development and severity of arthritis. Pathologic changes were examined by histology and radiography. The effects of Nur77 overexpression on immune responses were evaluated by cytokine production in vitro and serum levels of CII-specific antibodies. Sensitivity of T cells to apoptosis induction was analyzed in vitro following stimulation with anti-CD3 monoclonal antibody or glucocorticoid. Results The incidence and severity of CIA was significantly decreased in Nur77-transgenic mice compared with wild-type controls. Attenuation of the disease was associated with increased apoptosis induction in transgenic T cells and decreased production of CII-specific IgG2a antibodies in transgenic mice. Overexpression of Nur77 in the T cell compartment did not affect Th1/Th2 cytokine production or balance. Conclusion Nur77 overexpression in the T cell lineage attenuates the development and progression of CIA, probably by promoting activation-induced T cell apoptosis and by inhibiting CII-specific antibody production.

Urticarial vasculitis is a clinico-pathologic entity typified by recurrent episodes of urticaria that have the histopathologic features of leukocytoclastic vasculitis. The cutaneous features may include painful, burning or pruritic skin lesions, the persistence of individual lesions greater than 24 hours, palpable purpura, pronounced central clearing of lesions, and residual hyperpigmentation following resolution. However, because clinical characteristics of urticarial vasculitis may overlap with those of allergic urticaria, confirmation of the diagnosis requires a lesional skin biopsy. This condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome. In idiopathic urticarial vasculitis common laboratory findings are an elevation of erythrocyte sedimentation rate and reduction of serum complement. An association between urticarial vasculitis and systemic lupus erythematosus has been hypothesized as some clinical manifestations of disease overlap and C1q autoantibodies may be present in both diseases. Normo-complementemic patients usually have minimal or no systemic involvement and often have a better prognosis. On-the-other-hand, hypocomplementemic patients have the propensity to have more severe multi-organ involvement. Response to treatment is variable and a wide variety of therapeutic agents may be efficacious. Initial recommendations for treatment of urticarial vasculitis manifest only as non-necrotizing skin lesions include antihistamines, dapsone, colchicine, hydroxychloroquine or indomethacin, but corticosteroids are often required. With necrotizing skin lesions or visceral involvement, corticosteroids are regularly indicated. Cases of severe corticosteroid resistant urticarial vasculitis or where corticosteroid morbidity is evident [table: see text] may require treatment with other immunosuppressive agents such as azathioprine, cyclophosphamide, or cyclosporine.

Background: In general, T cells from normal, nonatopic individuals respond to aeroallergens with synthesis and release of IFN-γ. In contrast, release of T H 2-type cytokines by activated lymphocytes is a feature of allergic rhinitis and atopic asthma. Objective: The purpose of this study was to determine differences in T-cell recognition of epitopes within allergenic sequences, in terms of proliferation and cytokine production, in subjects with atopic asthma compared with subjects with allergic rhinitis and normal controls. Methods: Proliferative responses and IL-5/IFN-γ release patterns from PBMCs from cat-allergic asthmatic, cat-allergic rhinitic, and non–cat-allergic asthmatic subjects and nonatopic normal controls were determined in primary cultures. Cells were challenged with 7 overlapping peptides spanning chain 1 of the major cat allergen, Fel d 1. Results: The 4 groups did not differ with respect to the ability to mount proliferative responses to Fel d 1 peptides. In all groups, the IFN-γ responses were predominantly to the amino terminus peptides. Cat-allergic and non–cat-allergic asthmatic subjects (and not cat-allergic rhinitic subjects and normal controls) made IL-5 responses to most of the Fel d 1 peptides, the result being a mixed (T H 0) cytokine response at the N-terminus and a restricted (T H 2) response at the C-terminus. Conclusion: Proliferative and IL-5/IFN-γ responses of T cells from asthmatic and atopic rhinitic subjects and normal controls to allergen peptides can be dissociated. Furthermore, differing cytokine responses to peptides derived from a single antigen suggest that certain domains of the molecule might preferentially induce IL-5 rather than IFN-γ and as a result could be more important in disease pathogenesis. (J Allergy Clin Immunol 2001;108:349-56.)

Common variable immunodeficiency (CVID) is a primary immune defect typified by low levels of IgG, IgM, and IgA and poor antibody responses to carbohydrate and protein antigens that leads to increased risk of sinopulmonary infections [1]. The organisms responsible for these infections are typically encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae [2]. Effective treatment is replacement intravenous IgG [1]. Impaired antibody responses in CVID have been explained for some CVID patients by recent discoveries of genetic mutations and polymorphisms such as TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), CD19, and ICOS (inducible co-stimulator). However, these account for only 10% of CVID patients. For the remaining CVID patients, a molecular defect has not been identified [3, 4]. Toll-like receptors (TLRs) are pathogen-recognition receptors that are crucial for microbial elimination, whether through recruitment of phagocytes or activation of dendritic cells [5]. B cells also use TLRs as a means of activation and differentiation [3]. Of the 10 TLRs expressed in humans, B cells use TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. Of these, TLR7 and TLR9 are expressed in the endosomal compartment, whereas the other TLRs are expressed on the cell surface. TLR7 and TLR9 are expressed in low levels by naive B cells, and B-cell receptor (BCR) cross-linking leads to rapid upregulation of their expression [6]. Ligation of TLR7 and TLR9 can provide a signal for differentiation of B cells after antigenic stimulation through the BCR [7]. The ligand for TLR7 includes single-stranded RNA, and the ligand for TLR9 is CpG-ODN (CpG motifs in DNA oligodeoxynucleotides), which is more prevalent in prokaryotes. Defects in TLR7 and TLR9 have been reported for the B cells of CVID patients [3].

Background: IL-5 is central to the pathogenesis of airway eosinophilic inflammation and hyperresponsiveness associated with both atopic and nonatopic asthma. The therapeutic potential of IL-5 antagonists in asthma is supported by the inhibition of airway eosinophilia and hyperresponsiveness in animal models receiving neutralizing anti-IL-5 mAbs intravenously or intraperitoneally. Objective: The purpose of this study was to test the hypothesis that mAbs against IL-5 delivered by way of the respiratory tract are as effective as those delivered intraperitoneally in diminishing the pulmonary eosinophilic inflammation and airway hyperresponsiveness in a murine model of ovalbumin-induced asthma. Methods: Ovalbumin-sensitized Balb/c mice were given an anti–IL-5 mAb delivered intranasally or an isotype-matched control mAb delivered intranasally before respiratory challenge with ovalbumin. Outcome variables included respiratory system resistance responses to methacholine, bronchoalveolar lavage fluid cellularity, and lung histopathology. Results: Anti–IL-5 mAbs administered intranasally to ovalbumin-sensitized and challenged mice significantly decreased eosinophil counts in bronchoalveolar lavage fluid and lung tissue and significantly reduced airway hyperresponsiveness relative to ovalbumin-sensitized and challenged mice that received either no mAb treatment or an isotype-matched control mAb. Similar results were obtained when an anti–IL-5 mAb was given intraperitoneally. Conclusion: This is the first study to demonstrate that delivery of anti–IL-5 mAbs into the respiratory tract is efficacious in attenuating the asthma phenotype in a murine model. These results provide impetus for the development of inhaled IL-5 antagonists for the treatment of human asthma. (J Allergy Clin Immunol 1999;104:215-21.)

SUMMARY Grass pollen immunotherapy for the treatment of seasonal allergic rhinitis (‘summer hayfever’) results in improvement in symptoms, a reduction in the early and late phase responses to allergen provocation and decreased tissue eosinophilia. Immunotherapy may act by altering the pattern of cytokine production by allergen-specific T cells from a ‘Th2-type’ (IL-4 and IL-5) profile to a ‘Th1-type’ (interferon-gamma (IFN-γ)) profile. We set out to determine whether clinical improvement following specific allergen immunotherapy is accompanied by reduced production of the pro-eosinophilic and archetypal ‘Th2-type’ cytokine, IL-5. Peripheral blood mononuclear cells (PBMC) were isolated from (i) 13 patients who had received 6 or 7 years' continuous conventional immunotherapy with timothy grass pollen (Phleum pratense); (ii) 14 patients who had received 3 or 4 years of conventional immunotherapy followed by 3 years of placebo treatment; (iii) 12 matched seasonal rhinitic patients who had never received immunotherapy; and (iv) 17 non-atopic normal controls. PBMC were stimulated with 20 μg/ml and 200 μg/ml P. pratense extract, or 10 μg/ml of Mycobacterium tuberculosis purified protein derivative (PPD), at 2 × 106 cells/ml and 5 × 106 cells/ml. IL-5 concentrations in culture supernatants collected after 6 days' culture were measured by ELISA. IL-5 production in response to stimulation with P. pratense extract was highly reproducible and was elevated in both of the immunotherapy treated groups and the untreated rhinitics relative to non-atopic controls (P

Bronchial antigen challenge of sensitized atopic patients with asthma results in an early fall in FEV1, followed in a proportion of patients by a late (4 to 24 hours) fall. The late response is accompanied by an increase in bronchial reactivity, which is widely believed to reflect local influx and degranulation of inflammatory cells, particularly eosinophils, in association with elevated local secretion of cytokines. We hypothesized that the development of a late-phase bronchoconstrictor response and airway eosinophilia after allergen challenge of sensitized atopic patients with asthma is associated with elevated induced sputum concentrations of the eosinophil-active cytokines IL-5 and granulocyte-macrophage colony-stimulating factor and the proinflammatory cytokine tumor necrosis factor-alpha. We counted inflammatory leukocytes and measured cytokine concentrations in induced sputum at baseline and 24 hours after inhalational allergen challenge of 15 atopic patients with asthma who had previously demonstrated a late response. We observed significant increases in the numbers of eosinophils and the concentrations of their granule products, eosinophil cationic protein and eosinophil peroxidase. In contrast, the numbers of neutrophils and concentrations of two of their products, myeloperoxidase and human neutrophil lipocalin, did not significantly change. The numbers of sputum eosinophils correlated with the maximal late-phase fall in FEV1. Concentrations of IL-5 and tumor necrosis factor-alpha, but not granulocyte-macrophage colony-stimulating factor, were significantly elevated after allergen challenge. We conclude that the relatively noninvasive technique of induced sputum production can be used to monitor the effect of bronchial provocation on cytokine concentrations in asthma.

Basophils have emerged in recent years as a small but potent subpopulation of leukocytes capable of bridging innate and adaptive immunity. They can be activated through IgE-dependent and IgE-independent mechanisms to release preformed mediators and to produce Th2 cytokines. In addition to their role in protective immunity to helminths, basophils are major participants in allergic reactions as diverse as anaphylaxis and immediate hypersensitivity reactions, late-phase hypersensitivity reactions, and delayed hypersensitivity reactions. Additionally, basophils have been implicated in the pathophysiology of autoimmune diseases such as lupus nephritis and rheumatoid arthritis, and the modulation of immune responses to bacterial infections, as well as being a feature of myelogenous leukemias. Distinct signals for activation, degranulation, transendothelial migration, and immune regulation are being defined, and demonstrate the important role of basophils in promoting a Th2 microenvironment. These mechanistic insights are driving innovative approaches for diagnostic testing and therapeutic targeting of basophils.

The eosinophil is a multifunctional granulocyte best known for providing host defense against parasites. Paradoxically, eosinophils are also implicated in the pathogenesis of allergic inflammation, asthma, and hypereosinophilic syndromes. Emerging evidence also supports the potential for harnessing the cytotoxic power of eosinophils and redirecting it to kill solid tumors. Central to eosinophil physiology is interleukin-5 (IL-5) and its receptor (IL-5R) which is composed of a ligand-specific alpha chain (IL-5Rα) and the common beta chain (βc). Eosinophil activation can lead to their degranulation, resulting in rapid release of an arsenal of tissue-destructive proinflammatory mediators and cytotoxic proteins that can be both beneficial and detrimental to the host. This review discusses eosinophil immunobiology and therapeutic strategies for targeting of IL-5 and IL-5R, as well as the potential for harnessing eosinophil cytotoxicity as a tumoricide.

Pulmonary alveolar proteinosis (PAP) is a rare disease of the lung characterized by the accumulation of surfactant-derived lipoproteins within pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and increased infections. The disease is caused by a disruption in surfactant catabolism by alveolar macrophages due to loss of functional granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. The underlying molecular mechanisms causing deficiencies in GM-CSF signaling are as follows: 1) high levels of neutralizing GM-CSF autoantibodies observed in autoimmune PAP; 2) mutations in CSF2RA, the gene encoding the alpha chain of the GM-CSF receptor, observed in hereditary PAP; and 3) reduced numbers and function of alveolar macrophages as a result of other clinical diseases seen in secondary PAP. Recent studies investigating the biology of GM-CSF have revealed that not only does this cytokine have an indispensable role in lung physiology, but it is also a critical regulator of innate immunity and lung host defense.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that has recently been implicated as central to the microenvironment and is permissive for the immunologic cascade that initiates and propagates allergic immune responses. In humans, TSLP is produced predominantly by epithelial cells and activated mast cells, and stimulates myeloid dendritic cells (mDC), which uniquely express the heterodimeric TSLP receptor. TSLP-activated mDC can promote naive CD4+ T cells to differentiate into a Th2 phenotype and can promote the expansion of CD4+ Th2 memory cells. Recent evidence implicates TSLP as playing a pivotal role in the pathobiology of allergic asthma and atopic dermatitis. The potential for TSLP to provide a new therapeutic target for the treatment of allergic disorders is compelling, and elucidating the mechanisms that regulate TSLP expression and the effects of TSLP on orchestrating the immune response toward a Th2 phenotype should facilitate this quest.

Herein we report a patient with Behçet's like syndrome, idiopathic CD4+ T-lymphocytopenia, opportunistic infections, and a large polyclonal population of TCR alpha beta + CD4- CD8- T cells. Microfluorimetric analysis of peripheral blood mononuclear cells revealed CD4+ T-cell counts of 10 +/- 5/mm3. The CD3+ T cells were 99% TCR alpha beta +, of which 74 +/- 5% were CD4- CD8-. No clonal populations were detected by southern analysis for T-cell receptor V beta gene rearrangements. No evidence of human immunodeficiency virus infection was present, although nocardia, candida, pneumocystis, cytomegalovirus, and herpes infections were documented. The concomitant presence of opportunistic infections and a large population of TCR alpha beta + CD4- CD8- T cells suggests a pathogenic association and an intense immune response to microbial lipid or lipoglycan antigens presented in the context of CD1 molecules. This case demonstrates the potential for idiopathic CD4+ T-lymphocytopenia to occur in Behçet's-like syndrome with lethal consequences.

Pathophysiology of airway inflammation in asthma, Paula J. Busse and William W. Busse primary human lung cells in the evaluation of airway determination, Tannishia Goggans and Serpil C. Erzurum airway pH homeostasis in asthma and other inflammatory lung diseases, John Hunt and Benjamin Gaston monitoring of exhaled breath to assess airway inflammation in asthma, Peter J. Barnes the modulatory effects of carbon monoxide on the inflammatory response, Francis Whalen, Augustine M.K. Choi, and Jigme M. Sethi reactive nitrogen species and tyrosine nitration in airway inflammation, Albert van der Vliet, Jason P. Eiserich, Brian Morrissey, and Carroll E. Cross S-nitrosothiols in lung inflammation, Harvey E. Marshall, Loretta G. Que, Jonathan S. Stamler and Benjamin Gaston contribution of different nitric oxide synthase isoforms to allergen-induced airway hyperresponsiveness and inflammation - lessons from murine models, George T. DeSanctis and El-Bdaoui Haddad molecular mechanisms of increased nitric oxide airway inflammation, Weiling Xu and Serpil C. Erzurum regulation of nitric oxide synthesis by inducible nitric oxide synthase, Pawel Kolodziejski and N. Tony Eissa novel strategies for selective inhibition of inducible nitric oxide synthase, John F. Parkinson leukocyte recruitment in allergic pulmonary inflammation, Bruce S. Bochner neutrophil emigration in the lungs, Claire M. Doerschuk dendritic cells , A. Karolina Palucka and Jacques Banchereau the roles of mast cells in airway hyper-reactivity, inflammation and remodelling and immunoregulation in asthma, John L. Faul and Stephen J. Galli mast cells exocytosis in airway inflammation, Roberto Adachi, Rupesh Nigam, and Burton Dickey. (Part contents).

For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T(H)2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T(H)2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T(H)2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.

In the midst of an examination room cluttered with crayons, coloring books, and toys intended to pacify or bribe children during allergy skin testing, an anxious mother attended to her active 4-year-old son. A glance at the appointment book before walking into the room indicated that the reason for this new patient visit was “food allergies.” The interview began with the usual “why are you here” question. The mother’s response: she wanted to know what foods her son was really allergic to and were causing his hyperactivity (attention-deficit/ hyperactivity disorder [ADHD]). An Internet search had directed her to various blogs and support groups encouraging her to have her son tested for allergies. She found a physician who promised that one easy blood test could determine the best elimination diet to treat ADHD. The test results showed that he was allergic to “many things,” most of which he had eaten on a regular basis without any apparent reaction. However, she heeded the advice of her Internet ADHD “expert” and began to eliminate the foods from his diet. During the office visit, she said that she saw no difference in his behavior on the various elimination diets. In fact, she thought that his behavior had gotten worse because he could not eat his favorite foods. Yet she was worried that reintroducing the foods might be harmful.

Objective This paper reviews the current views of the pathogenesis of airway eosinophilic inflammation and airway hyperresponsiveness (AHR) in allergic asthma based on mouse models of the disease. The reader will also encounter new treatment strategies that have arisen as this knowledge is applied in practice. Data Sources MEDLINE searches were conducted with key words asthma , mouse model , and murine . Additional articles were identified from references in articles and book chapters. Study Selection Original research papers and review articles from peer-reviewed journals were chosen. Results Although the mouse model does not replicate human asthma exactly, the lessons learned about the pathogenesis of allergic airway inflammation and AHR are generally applicable in humans. Type 2 T helper lymphocytes (Th2) orchestrate the inflammation and are crucial for the development of AHR. Cells and molecules involved in T cell activation (dendritic cells, T cell receptor, major histocompatibility complex molecule, and costimulatory molecules) are also vital. Besides these, no other cell or molecule could be shown to be indispensable for the establishment of the model under all experimental conditions. There are at least three pathways that lead to AHR. One is dependent on immunoglobulin E and mast cells, one on eosinophils and interleukin-5 (IL-5), and one on IL-13. Eosinophils are probably the most important effector cells of AHR. Radical methods to treat asthma have been tested in the animal model, including modifying the polarity of lymphocyte response and antagonizing IL-5. Conclusions AHR, the hallmark of asthma, is attributable to airway inflammation ultimately mediated by helper T cells via three pathways, at least. The mouse model is also a valuable testing ground for new therapies of asthma.

Amyloidosis typically manifests with disseminated infiltration of multiple organ systems. Rarely, amyloidosis may be localized. We report a patient with localized subcutaneous nodular amyloidosis, without systemic amyloid involvement or myeloma, whose presenting symptom was multiple discrete neck nodules. Immunohistochemical analysis showed the amyloid deposits to be derived from lambda light chains. Twenty-four month follow-up showed minimal disease progression. A literature review showed only 5 reported cases of subcutaneous nodular amyloidosis. This is the first description of a patient with subcutaneous nodular amyloidosis derived from lambda light chains. HUM PATHOL 32:346-348.

Background: IL-5-producing allergen-specific T cells are thought to play a prominent role in the pathogenesis of allergic inflammation. We hypothesized that T cell allergen-driven IL-5 synthesis is elevated in patients with atopic disease as compared with that in atopic patients free of disease and nonatopic control subjects. Objectives: The purpose of this study was to compare IL-5 and interferon-γ (IFN-γ) secretion and proliferation by peripheral blood T cells from sensitized atopic patients with asthma, rhinitis, and no symptoms and from nonatopic control subjects in response to the allergen Dermatophagoides pteronyssinus (Der p) and the control recall antigen Mycobacterium tuberculosis purified protein derivative (PPD). Methods: To measure allergen-induced IL-5 production and proliferation, we developed a short-term culture technique that required a single antigenic stimulation of freshly isolated peripheral blood mononuclear cells (PBMC). With this technique, we measured Der p- and PPD-induced IL-5 production and proliferation in PBMC from atopic patients with asthma who were allergic to Der p, atopic patients with rhinitis, atopic patients with no symptoms, and a group of nonatopic normal control subjects. In four experiments, CD4+ or CD8+ T cells were depleted from PBMC to confirm that IL-5 synthesis was T cell dependent. Results: T cell IL-5 production, but not IFN-γ production, in response to Der p was elevated in atopic patients with asthma and atopic patients with rhinitis compared with findings in atopic patients with no symptoms or nonatopic control subjects. IL-5 production was abrogated by depletion of CD4+, but not CD8+, T cells. In subjects with asthma, allergen-driven IL-5 production correlated with bronchial hyperreactivity. Allergen-induced proliferation was also higher in patients with asthma than in atopic subjects with no symptoms or nonatopic controls. T cell IL-5 and IFN-γ production and proliferation in response to PPD were similar regardless of atopic status or disease. Conclusions: Elevated IL-5 production is a characteristic of allergen-specific peripheral blood CD4+ T cells from sensitized patients with atopic disease but not atopy per se. (J Allergy Clin Immunol 1997;99:563-9.)

In B-cell chronic lymphocytic leukemia, neoplastic B-lymphocytes are arrested in development. Since interleukins are essential for B-cell differentiation, we examined whether B-CLL cells were capable of responding normally to interleukins. Purified B-lymphocytes from B-CLL patients and controls were compared for their ability to proliferate and differentiate after stimulation with MCAT or SAC plus rhIL-2 or rhIL-5. When rhIL-5 was added to MCAT-stimulated cells, 8 of 10 controls showed a substantial increase in IgM production, compared with only 1 of 10 B-CLL patients. Lack of IL-5 responsiveness could provide insight into the arrested B-lymphocyte development of some B-CLL patients.

Urticaria and angioedema are usually the clinical consequence of vasoactive mediators derived from mast cells in the skin or mucosal tissues. Efforts to classify mast cell-mediated causes of urticaria and angioedema have generally been frustrated by their diverse pathogenesis and clinical course. The term acute is typically used to describe fleeting lesions whose recurrence does not extend beyond 6 weeks. Chronic is the term used to describe lesions that persist for more than a few hours but usually less than a day, and recurrences extend for more than 6 weeks. These definitions do not take histology into account. Skin biopsies of fleeting lesions demonstrate a paucity of inflammatory cells, whereas more persistent lesions display a spectrum of perivascular cuffing by predominantly T cells and monocytes. The presence of leukocytoclastic vasculitis in persistent lesions indicates an underlying immune complex disease. Many of the physical urticarias have fleeting lesions that can be induced with the appropriate stimulus for years. This review article has emphasized the clinical course and histology of urticaria and angioedema lesions in an effort to provide a more complete understanding of the pathogenesis and appropriate treatment. Clearly, avoidance of an identifiable inciting stimulus is optimum management, although most patients have no etiology defined or the cause is not realistically avoidable. At present, treatment options for these patients rely on antihistamines to control the immediate consequence of mast cell degranulation. Corticosteroids are reserved for the treatment of patients whose urticaria or angioedema lesions persist, reflecting the increasing involvement of mononuclear cells in the disease process. For leukocytoclastic vasculitis, corticosteroids are indicated, and cytotoxic drugs may be required for adequate treatment. Future treatments of urticaria and angioedema will evolve based on elucidation of the relevant cells and soluble mediators and will include counterregulatory or antagonistic peptides and drugs. C1 esterase inhibitor deficiency is a relatively uncommon cause of angioedema but is important to understand because of its ability to clinically mimic mast cell-mediated angioedemas and its unique pathogenesis and treatment. HAE can be divided into two serologic subtypes that simply reflect the location of the defect in one of the codominantly expressed C1-INH genes on chromosome 11. AAE can be divided into two serologic subtypes. AAE type I is due to massive consumption of C1-INH, presumably by tumor-related immune complexes. AAE type II is due to an anti-C1-INH autoantibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Article de synthese sur les syndromes d'immunodeficits primaires en immunoglobulines: immunodeficit hereditaire de Bruton, immunodeficit commun variable, immunodeficit en IgA secretee, en sous classes d'IgG, en IgM, diagnostic et traitement

Sustained and significant reversal of antibody deficiencies is uncommon, although it has been noted in some cases during childhood and after viral infections. We report a case of reversal of IgG2 deficiency after splenectomy. A 46-year-old man who suffered recurrent sinusitis despite antibiotic therapy was noted to have IgG2 deficiency and cutaneous anergy. Replacement therapy with intravenous immunoglobulin ameliorated his symptoms. After 13 months of therapy, the patient had a diagnostic laparotomy and splenectomy because of portal hypertension, hypersplenism, and consideration of underlying malignancy. No evidence of malignancy or infection, including human immunodeficiency virus, active cytomegalovirus, or Epstein-Barr virus infection, was found. After splenectomy, the patient's serum IgG2 level normalized without replacement therapy. Subsequently, it fell, then normalized once more, and remains normal. The patient also demonstrated positive reactions to delayed hypersensitivity testing after splenectomy, but, subsequently, became anergic and remains anergic at the present time. Since the splenectomy he has remained clinically well without antibiotics or immunoglobulin replacement. In vitro analysis of his lymphocyte function demonstrated impaired T cell proliferation as well as an intrinsic B cell differentiation defect. This case demonstrates the potentially dynamic nature of IgG subclass deficiencies.

This Update in Allergy and Immunology covers 3 themes: mechanisms of allergic disease, with insight into pathogenesis or treatment; therapy for allergic disease, including controversial or novel ap...

Although the activation of eosinophils by cytokines has been reported s' 9 and several authors have found increased lymphocyte proliferation to food antigens in patients with food allergy, 1~ these data have not yet been reported in patients with pulmonary hemosiderosis. We propose that in this case a specific activation mechanism in sensitized T cells may have taken place and these cells may have released cytokines that activate eosinophils, basophils, and/or mast cells. Therefore in patients with IPH in whom milk allergy may trigger or aggravate pulmonary damage, controlled administration of milk proteins with quantitation of different inflammatory mediators may help to establish a causal relationship.

Rationale It has recently been shown that leptin a hormone that controls body weight, also regulates autoimmunity. We examined the role of leptin in collagen-induced arthritis (CIA) an animal model of human rheumatoid arthritis. Methods Serum was obtained from normal DBA male and female mice and leptin level was measured. CIA was induced in wild-type DBA (H-2 q ), wild-type C57BL/6 (H-2 b ), and Bcl-x L transgenic (H-2 b ) mice and their levels of serum leptin were measured prior to the onset of arthritis and at the peak time of arthritis. Results Leptin level in DBA mice prior to induction of arthritis was significantly higher (p L transgenic mice when compared to wild-type controls, consistent with the clinical severity of arthritis which was also significantly greater in the Bcl-x L transgenic group. Conclusions Serum leptin levels appear to correlate with the induction of CIA, in that leptin levels increased just prior to the onset of arthritis. There also appears to be a correlation between the degree of leptin surge and the severity of subsequent clinical arthritis.

Amyloidosis occurs in a significant proportion of patients with rheumatologic diseases. The fibrillar amyloid proteins in such patients are composed predominantly of amyloid A protein, which is characteristic of the amyloid deposits associated with chronic inflammatory diseases. Only four patients with amyloidosis associated with systemic lupus erythematosus (SLE) have been described previously; analyses of their fibrillar amyloid proteins were not reported. We present herein, a patient with SLE and amyloidosis. Histochemical staining of our patient's renal tissue with Congo red demonstrated that the amyloid deposits contained amyloid A protein, as defined by permanganate sensitivity. In addition, the patient's serum contained increased concentrations of serum amyloid A proteins. In review, each of the previously described patients with amyloidosis associated with SLE had renal amyloid deposits, with diagnosis in three during evaluation of proteinuria. Thus, although rare, amyloidosis should be considered in the differential diagnosis of proteinuria in patients with SLE.

Cytotoxic lymphocyte (CTL) responses of unprimed NZB spleen cells peaked on day 4 of culture as did cells from primed NZB or BALB/c mice. In contrast, primary BALB/c and DBA/2 responses peaked on day 6 of culture. Thus, NZB CTL generation was similar to the accelerated in vitro generation of CTL from the spleen cells of alloantigen-primed NZB and BALB/c mice. To evaluate the kinetics of these CTL responses, multiple-time-point analyses were performed during the initial 90 min of the 51Cr-release assays. Analyses were done on days 4 and 6. On day 4, NZB CTL had an initial velocity of lysis slightly greater than that of BALB/c or DBA/2 CTL; however, it was far less than that of secondary NZB and secondary BALB/c CTL. These studies indicate that NZB mice can generate primary CTL responses at an accelerated rate. Such augmented primary responses are unique and may explain recently described abnormal NZB T cell recognition as well as resistance of NZB CTL to suppressor signals.

• A 48-year-old woman had a variation of the syndrome of polyneuropathy, organomegaly, endocrinopathy,Mprotein, and skin changes (the so-called POEMS syndrome). The patient's neurological findings were entirely normal, but she had splenomegaly, hyperprolactinemia with galactorrhea and oligomenorrhea, a thyroid nodule with evidence of mild thyroiditis on aspiration biopsy specimen, an IgG-κ monoclonal gammopathy, and hyperpigmentation and thickening of the skin. A short course of plasmapheresis (twelve 4-L exchanges in one month) did not alter any of the clinical abnormalities, but did result in a 70% decrease in the monoclonal IgG level (from 2.2 to 0.7 g/dL). (Arch Intern Med1982;142:1231-1234)

The efficacy of nifedipine, a calcium channel antagonist, in the treatment of chronic idiopathic urticaria, was evaluated in a double-blinded, placebo-controlled, crossover trial. Ten patients with chronic urticaria refractory to maximally tolerated doses of H1 and H2 antihistamines and in whom extensive evaluation failed to identify a cause for their urticaria were entered into the study. Patients continued with their prestudy antihistamine regimens. A study drug dosage was titrated in each patient and maintained throughout the trial. Patients were treated with placebo or nifedipine for 4 weeks and then crossed over to the other medication for 4 weeks. One patient withdrew because of unrelated medical illness, two patients withdrew after crossover to placebo because of intolerable urticaria, and seven patients completed the study. A beneficial effect of nifedipine was clearly demonstrated. Hive count, hive index, and itch index were all significantly improved at the end of 4 weeks of nifedipine treatment (p = 0.023, 0.003, and 0.003, respectively) but not placebo treatment (p = 0.194, 0.664, and 0.944, respectively). Additionally, end point hive index and itch index scores with nifedipine compared to corresponding placebo scores were significantly improved (p = 0.010 and 0.008, respectively). Nifedipine was well tolerated. Thus, when nifedipine is used as an adjunct to antihistamines, it appears to be a safe, efficacious drug for the treatment of chronic idiopathic urticaria.

This is the first reported case of thyroid storm complicated by rhabdomyolysis with acute reversible renal failure. The only possible causes for the rhabdomyolysis were Inherent features of thyroid storm. Although hyperthyroid patients characteristically have normal or low serum levels of muscle enzymes, this case report demonstrates that rhabdomyolysis with elevated serum levels of muscle enzymes can occur with hyperthyroidism. An appreciation of the potential for rhabdomyolysis in hyperthyroidism should facilitate prompt initiation of aggressive therapy for myoglobinuria and thereby limit the severity of acute renal failure in these already very sick patients.

Piperacillin is being used with increasing frequency as an important antibiotic for the treatment of severe and life-threatening infections. Many of these patients may have multiple possible causes of leukopenia and/or anemia. An awareness of the potential for piperacillin to cause the rapid onset of leukopenia and/or anemia may have important therapeutic implications, especially in severely ill patients.

• Moderate-dose (15 to 20 mg/kg) bolus intravenous (IV) cyclophosphamide is increasingly being employed for the treatment of autoimmune diseases. High-dose (30 to 50 mg/kg) IV cyclophosphamide, which is used in transplantation and oncology, may cause water intolerance and water intoxication. Described herein is the first patient, to our knowledge, to develop water intoxication following administration of moderate-dose IV cyclophosphamide. A water challenge test demonstrated the absence of an underlying syndrome of inappropriate antidiuretic hormone secretion. Water intolerance was demonstrated in five additional patients receiving moderate-dose IV cyclophosphamide and hydration with hypotonic fluids. Thus, contrary to previous reports, water intoxication can occur following administration of moderate-dose IV cyclophosphamide. Patients with renal insufficiency who are receiving hypotonic fluids following moderate-dose IV cyclophosphamide administration may be at greatest risk for development of symptomatic water intoxication. (Arch Intern Med1985;145:548-549)

In Reply.— The letter from Dr Krause, regarding the report by Riccardi 1 of decreased rate of neurofibroma growth observed during treatment with ketotifen, addresses the fundamental question of ketotifen therapeutic mechanisms in the treatment of neurofibromatosis. Specifically, Dr Krause raises concerns about the evidence that ketotifen can stabilize mast cells in vivo and, hence, the potential for mast-cell blockers to be important in the treatment of neurofibromatosis. Ketotifen has been shown to have several effects on mast cells in vitro. First, ketotifen has antihistamine activity as an H-1 receptor antagonist. 2,3 Second, ketotifen can prevent mast-cell degranulation as determined by membrane-triggered histamine release. 2,3 Third, ketotifen can prevent calcium flux across the cell membrane. 4 Evidence that ketotifen can prevent mast-cell degranulation in vivo is presented in the report by Huston et al 5 regarding three patients with physical urticarias. Dr Krause raises a concern regarding the observations of Huston and